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Sunday, August 10, 2025

CD20 monoclonal antibodies


1. Introduction

  • CD20 monoclonal antibodies are targeted biologic agents that bind to the CD20 antigen on B lymphocytes.

  • Used in the treatment of B-cell malignancies and autoimmune diseases.

  • Include both type I (rituximab, ofatumumab, obinutuzumab) and type II (obinutuzumab) antibodies, with differences in binding orientation and cytotoxicity mechanisms.

2. Target: CD20 Antigen

  • CD20 is a non-glycosylated phosphoprotein expressed on the surface of:

    • Pre-B cells.

    • Mature B lymphocytes.

    • Most malignant B cells.

  • Not present on hematopoietic stem cells, pro-B cells, plasma cells, or other normal tissues.

  • Functions:

    • Regulates B-cell activation and calcium influx.

    • Serves as an ideal therapeutic target because it is stably expressed during most of the B-cell life span and is not shed into circulation.

3. Mechanism of Action

  • Bind specifically to CD20 on B cells and mediate cytotoxicity via:

    • Antibody-dependent cellular cytotoxicity (ADCC): NK cells, macrophages destroy tagged cells.

    • Complement-dependent cytotoxicity (CDC): activation of complement cascade leads to cell lysis.

    • Direct apoptosis: signaling through CD20 can trigger programmed cell death.

  • Depletion of circulating and tissue B cells leads to therapeutic effects in cancer and autoimmunity.

4. Approved CD20 Monoclonal Antibodies

Rituximab

  • Chimeric IgG1 type I antibody.

  • Used in oncology and autoimmune conditions.

Obinutuzumab

  • Humanized IgG1 type II antibody; glycoengineered for enhanced ADCC.

  • Less complement activation, more direct cell death induction.

Ofatumumab

  • Fully human IgG1 type I antibody; binds a distinct CD20 epitope.

Other agents

  • Ublituximab (recent approval in some regions).

  • Investigational biosimilars and next-generation CD20 antibodies.

5. Pharmacokinetics

  • Route: Intravenous infusion for most; ofatumumab is also available as subcutaneous injection (multiple sclerosis).

  • Distribution: confined largely to vascular and interstitial spaces; targets CD20-positive cells in blood, lymphoid tissue, and marrow.

  • Metabolism: degraded to peptides and amino acids via normal protein catabolism.

  • Half-life: increases after initial doses as target cells are depleted (from days to weeks).

6. Clinical Indications

Hematologic malignancies

  • Non-Hodgkin lymphoma (NHL).

  • Chronic lymphocytic leukemia (CLL).

  • Follicular lymphoma.

  • Diffuse large B-cell lymphoma (DLBCL).

  • Mantle cell lymphoma.

Autoimmune diseases

  • Rheumatoid arthritis (rituximab in combination with methotrexate after inadequate TNF-inhibitor response).

  • Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA).

  • Multiple sclerosis (ofatumumab and ocrelizumab).

7. Dosing and Administration (Examples)

Rituximab

  • Oncology: 375 mg/m² IV once weekly × 4 doses or in cycles with chemotherapy.

  • Autoimmune: two 1,000 mg IV doses separated by 2 weeks, repeated every 6–12 months.

Obinutuzumab

  • Often given in combination with chlorambucil or bendamustine in CLL/NHL; infusion split over days 1–2 for first cycle to reduce reaction risk.

Ofatumumab

  • CLL: IV infusion starting at 300 mg, escalating to 2,000 mg weekly, then monthly.

  • Multiple sclerosis: fixed-dose subcutaneous injections monthly after loading.

8. Adverse Effects

Infusion-related reactions

  • Fever, chills, rigors, hypotension, rash, bronchospasm; most frequent with first infusion.

Hematologic

  • Neutropenia, thrombocytopenia, anemia.

Infections

  • Bacterial, viral, fungal infections; reactivation of hepatitis B virus (HBV) and progressive multifocal leukoencephalopathy (PML).

Other

  • Fatigue, nausea, diarrhea.

  • Rare: severe mucocutaneous reactions (e.g., Stevens–Johnson syndrome).

9. Contraindications and Precautions

  • Hypersensitivity to the drug or excipients.

  • Active severe infections.

  • Screening for HBV required before initiation; prophylaxis if positive.

  • Use with caution in patients with cardiovascular disease (infusion reactions may cause hemodynamic instability).

  • Pregnancy: potential fetal B-cell depletion; contraception required during and after therapy.

  • Avoid live vaccines during and for months after treatment.

10. Drug Interactions

  • No major CYP450 interactions (monoclonal antibodies are not enzyme-metabolized).

  • Concomitant immunosuppressants increase infection risk.

  • Vaccines: reduced immune response; live vaccines contraindicated.

11. Monitoring Requirements

  • CBC with differential before and during therapy.

  • HBV screening and ongoing monitoring in at-risk patients.

  • Monitor for infusion-related reactions during administration.

  • Assess for signs of infection and neurological changes (PML risk).

12. Advantages and Limitations

Advantages

  • Highly specific for malignant and autoreactive B cells.

  • Multiple mechanisms of cytotoxicity.

  • Long duration of B-cell depletion after a short treatment course.

Limitations

  • Infusion reactions common at initiation.

  • Risk of serious infections and viral reactivation.

  • High cost; requires specialized administration and monitoring




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